Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies characterized by dysplastic and ineffective hematopoiesis. MDS bone marrow precursors have a larger cell size, deregulated proliferation and maturation, and accelerated attrition by programmed cell death (List A, et al. N Engl J Med. 2005 352(6):549-57; Span L. F, et al. Leuk Res. 2007 31(12):1659-67; Garcia-Manero G. Am J Hematol. 2014 89(1):97-108). Despite these shared phenotypes, MDS harbor a spectrum of clonal chromosome abnormalities and somatic gene mutations, the latter most commonly involving genes encoding RNA splicing and epigenetic regulatory proteins (Bejar R, et al. J Clin Oncol. 2011 29(5):504-15; Yoshida K, et al. Nature. 2011 478(7367):64-9). How such diverse genetic events initiate a common MDS phenotype is unexplained.